Two tablets contain: Vitamin E (as d-alpha tocopheryl acid succinate) 200 IU • Zinc (as zinc monomethionine) 10 mg • L-Arginine (as l-arginine HCl) 500 mg • Mucuna seed extract (15% l-dopa equal to 45 mg and 20% catecholamines equal to 60 mg) 300 mg • Tribulus terrestris fruit/root 10:1 extract (40% saponins equal to 100 mg) 250 mg • Yohimbe bark extract (9% yohimbine equal to 10 mg) 111.2 mg • Horny Goat Weed whole plant (epimedium grandiflorum) 100 mg • Potency Wood root 4:1 extract (muira puama) 50 mg • Korean Red Ginseng root 10:1 extract (panax ginseng) 20 mg. Other Ingredients: Cellulose, Stearic Acid, Magnesium Stearate, Silica, Cellulose and Glycerin Coating, Vanilla.
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
Below is general information about the effectiveness of the known ingredients contained in the product Action Max XXXtreme. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product Action Max XXXtreme. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
POSSIBLY SAFE ...when used orally and appropriately. Powdered formulations of cowhage seed that are standardized to provide levodopa 75-400 mg daily have been used with apparent safety for up to 20 weeks (7020,7203,97266).
POSSIBLY UNSAFE ...when the hair of the cowhage bean pod is used orally or topically. The bean pod hairs are strong irritants and can cause severe itching, burning, and inflammation (18).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when horny goat weed extract is used orally and appropriately, short-term. A specific extract of horny goat weed containing 60 mg icariin, 15 mg daidzein, and 3 mg genistein (Xianling Gubao; Tong Ji Tang Pharmacal Company) has been used daily with apparent safety for up to 24 months (14900,97268). Another aqueous extract of horny goat weed containing up to 25.36% icariin has been used in a dose of 300 mL daily with apparent safety for up to 6 months (55452). Another horny goat weed extract has been used with apparent safety at doses up to 1000 mg daily (providing 200 mg icariin) for up to 30 days (108311).
POSSIBLY UNSAFE ...when used orally long-term or in high doses. Long-term use, or taking high doses of some species of horny goat weed, has been linked to serious adverse effects including respiratory arrest (10346).
PREGNANCY: POSSIBLY UNSAFE
when used orally.
Horny goat weed might have androgenic activity (10346). Theoretically, it might harm a developing fetus; avoid using.
LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately. L-arginine has been used safely in clinical studies at doses of up to 24 grams daily for up to 18 months (3331,3460,3595,3596,5531,5532,5533,6028,7815,7816)(8014,8473,13709,31943,91195,91196,91963,99264,99267,110380)(110387). A tolerable upper intake level (UL) for arginine has not been established, but the observed safe level (OSL) of arginine intake established in clinical research is 20 grams (31996). ...when used intravenously and appropriately. Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically and appropriately. L-arginine appears to be safe when 5 grams is applied as a topical cream twice daily for 2 weeks or when a dentifrice is used at a dose of 1.5% w/w for up to 2 years (14913,96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks (96807).
CHILDREN: POSSIBLY SAFE
when used orally in premature infants and children (8474,32286,96803,97392,110391).
...when used intravenously and appropriately (97392). Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically, short-term. A dentifrice containing L-arginine appears to be safe when used at a dose of 1.5% w/w for up to 2 years in children at least 3.7 years of age (96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks in children at least 13 years of age (96807).
CHILDREN: POSSIBLY UNSAFE
when used intravenously in high doses.
Parenteral L-arginine is an FDA-approved prescription product (15). However, when higher than recommended doses are used, injection site reactions, hypersensitivity reactions, hematuria, and death have occurred in children (16817).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term.
L-arginine 12 grams daily for 2 days has been used with apparent safety in pregnancy during the third trimester (11828). L-arginine 3 grams daily has been taken safely during the second and/or third trimesters (31938,110379,110382). ...when used intravenously and appropriately, short-term. Intravenous L-arginine 20-30 grams daily has been used safely in pregnancy for up to 5 days (31847,31933,31961,31978).
LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately, short-term. Taking muira puama 500-1050 mg daily, as part of a combination product, has been used with apparent safety for 1 month (63920,103224). There is insufficient reliable information available about the safety of muira puama when used long-term.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately, short-term. Panax ginseng seems to be safe when used for up to 6 months (8813,8814,17736,89741,89743,89745,89746,89747,89748,103044)(103477,114980,114981,114984,114985). Panax ginseng sprout extract has also been used with apparent safety in doses up to 450 mg daily for up to 12 weeks (114983).
POSSIBLY UNSAFE ...when used orally, long-term. There is some concern about the long-term safety due to potential hormone-like effects, which might cause adverse effects with prolonged use (12537). Tell patients to limit continuous use to less than 6 months. There is insufficient reliable information available about the safety of Panax ginseng when used topically.
CHILDREN: LIKELY UNSAFE
when used orally in infants.
Use of Panax ginseng in newborns is associated with intoxication that can lead to death (12). There is limited reliable information available about use in older children (24109,103049); avoid using.
PREGNANCY: POSSIBLY UNSAFE
when used orally.
Ginsenoside Rb1, an active constituent of Panax ginseng, has teratogenic effects in animal models (10447,24106,24107); avoid using.
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY UNSAFE ...when the spine-covered fruit is used orally. There have been reports of bilateral pneumothorax and bronchial polyp after oral consumption of the spine-covered fruit (818).
PREGNANCY: POSSIBLY UNSAFE
when used orally.
Animal research suggests that tribulus might adversely affect fetal development (12674); avoid using.
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally or topically and appropriately. Vitamin E is generally considered safe, even at doses exceeding the recommended dietary allowance (RDA); however, adverse effects are more likely to occur with higher doses. The tolerable upper intake level (UL) in healthy people is 1000 mg daily, equivalent to 1100 IU of synthetic vitamin E (all-rac-alpha-tocopherol) or 1500 IU of natural vitamin E (RRR-alpha-tocopherol) (4668,4681,4713,4714,4844,89234,90067,90069,90072,19206)(63244,97075). Although there is some concern that taking vitamin E in doses of 400 IU (form unspecified) per day or higher might increase the risk of adverse outcomes and mortality from all causes (12212,13036,15305,16709,83339), most of this evidence comes from studies that included middle-aged or older patients with chronic diseases or patients from developing countries in which nutritional deficiencies are prevalent.
POSSIBLY UNSAFE ...when used orally in high doses. Repeated doses exceeding the tolerable upper intake level (UL) of 1000 mg daily are associated with significant side effects in otherwise healthy people (4844). ...when used intravenously in large doses. Large repeated intravenous doses of all-rac-alpha-tocopherol (synthetic vitamin E) were associated with decreased activity of clotting factors and bleeding in one report (3074). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults who use e-cigarette, or vaping, products, which often contain vitamin E acetate. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Vitamin E acetate has been detected in most bronchoalveolar lavage samples taken from patients with EVALI. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. While this association shows a correlation between vitamin E acetate inhalation and lung injury, a causal link has not yet been determined, and it is not clear if other toxic compounds are also involved (101061,101062,102970).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Vitamin E has been safely used in children in amounts below the tolerable upper intake level (UL). The UL for healthy children is: 200 mg in children aged 1-3 years, 300 mg in children aged 4-8 years, 600 mg in children aged 9-13 years, and 800 mg in children aged 14-18 years. A UL has not been established for infants up to 12 months of age (23388).
CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL due to increased risk of adverse effects (23388).
...when alpha-tocopherol is used intravenously in large doses in premature infants. Large intravenous doses of vitamin E are associated with an increased risk of necrotizing enterocolitis and sepsis in this population (85062,85083). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adolescents and teenagers who use e-cigarette, or vaping, products. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Constituents in E-cigarette or vaping products with the potential to cause lung injury or impaired lung function include lipids, such as vitamin E acetate. Vitamin E acetate has been detected in all bronchoalveolar lavage samples taken from patients with EVALI. No other ingredient, including THC or nicotine, was found in all samples, and other ingredients, including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable This shows that vitamin E acetate is at the primary site of lung injury. A causal link has not yet been described and it is not clear if other compounds are also involved (101061,101062).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately.
The tolerable upper intake level (UL) during pregnancy is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older. However, maternal supplementation is not generally recommended unless dietary vitamin E falls below the RDA (4260). No serious adverse effects were reported with oral intake of 400 IU per day starting at weeks 9-22 of pregnancy in healthy patients or those at high risk for pre-eclampsia (3236,97075), or with 600-900 IU daily during the last two months of pregnancy (4260). However, some preliminary evidence suggests that taking vitamin E supplements might be harmful when taken in early pregnancy. A case-control study found that taking a vitamin E supplement during the first 8 weeks of pregnancy is associated with a 1.7-9-fold increase in odds of congenital heart defects (16823). However, the exact amount of vitamin E consumed during pregnancy in this study is unclear. Until more is known, advise patients to avoid taking a vitamin E supplement in early pregnancy unless needed for an appropriate medical indication.
LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL).
The UL during lactation is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older (4844).
LACTATION: POSSIBLY UNSAFE
when used orally in amounts that exceed the UL due to increased risk of adverse effects (4844).
POSSIBLY UNSAFE ...when used orally. Yohimbine, a constituent of yohimbe, has been associated with serious adverse effects including cardiac arrhythmia, agitation, myocardial infarction, seizure, and others (17465). Some research shows that yohimbine can be safely used under close medical supervision for up to 10 weeks (3305,3307,3311,3313). However, due to safety concerns, yohimbe should not be used without medical supervision.
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally.
Yohimbe might have uterine relaxant effects and also cause fetal toxicity (19).
LIKELY SAFE ...when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 40 mg daily (7135). ...when used topically and appropriately (2688,6538,6539,7135,8623,11051,111291).
POSSIBLY SAFE ...when used orally and appropriately in doses higher than the tolerable upper intake level (UL). Because the UL of zinc is based on regular daily intake, short-term excursions above 40 mg daily are not likely to be harmful. In fact, there is some evidence that doses of elemental zinc as high as 80 mg daily in combination with copper 2 mg can be used safely for approximately 6 years without significant adverse effects (7303,8622,92212). However, there is some concern that doses higher than the UL of 40 mg daily might decrease copper absorption and result in anemia (7135).
POSSIBLY UNSAFE ...when used intranasally. Case reports and animal research suggest that intranasal zinc might cause permanent anosmia or loss of sense of smell (11155,11156,11703,11704,11705,11706,11707,16800,16801,17083). Several hundred reports of anosmia have been submitted to the US Food and Drug Administration (FDA) and the manufacturer of some intranasal zinc products (Zicam) (16800,16801). Advise patients not to use intranasal zinc products.
LIKELY UNSAFE ...when taken orally in excessive amounts. Ingestion of 10-30 grams of zinc sulfate can be lethal in adults (7135). Chronic intake of 450-1600 mg daily can cause multiple forms of anemia, copper deficiency, and myeloneuropathies (7135,17092,17093,112473). This has been reported with use of zinc-containing denture adhesives in amounts exceeding the labeled directions, such as several times a day for several years (17092,17093). Advise patients to follow the label directions on denture adhesives that contain zinc.
CHILDREN: LIKELY SAFE
when used orally and appropriately (7135).
Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL for children is based on age: 4 mg daily for 0-6 months, 5 mg daily for 7-12 months, 7 mg daily for 1-3 years, 12 mg daily for 4-8 years, 23 mg daily for 9-13 years, and 34 mg daily for 14-18 years (7135,97140).
CHILDREN: POSSIBLY UNSAFE
when used orally in high doses.
Taking amounts greater than the UL can cause sideroblastic anemia and copper deficiency (7135). ...when used topically on damaged skin. An infant treated with 10% zinc oxide ointment for severe diaper rash with perianal erosions developed hyperzincemia. Absorption seemed to occur mainly via the erosions; plasma levels dropped after the erosions healed despite continued use of the ointment (106905).
PREGNANCY: LIKELY SAFE
when used orally and appropriately.
Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during pregnancy in those 14-18 years of age and 40 mg daily in those 19-50 years of age (7135).
PREGNANCY: LIKELY UNSAFE
when used orally in doses exceeding the UL (7135).
LACTATION: LIKELY SAFE
when used orally and appropriately.
Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during lactation in those 14-18 years of age, and 40 mg daily for those 19-50 years of age (7135).
LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL.
Higher doses can cause zinc-induced copper deficiency in nursing infants (7135).
Below is general information about the interactions of the known ingredients contained in the product Action Max XXXtreme. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Theoretically, concomitant use of cowhage and anesthesia might increase the risk of arrhythmias.
 Details
Cowhage contains levodopa (7020,7205,46334,46336,94723,94724). Use of levodopa with cyclopropane or halogenated hydrocarbon anesthesia has led to arrhythmias. Other anesthetics have not been implicated (15). Use other anesthetics in patients taking cowhage or tell patients to stop taking cowhage at least 2 weeks before surgery.
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Theoretically, concomitant use of cowhage and antidiabetes drugs might increase the risk of hypoglycemia.
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Animal research shows that cowhage might have hypoglycemic effects (7221).
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Theoretically, use of cowhage might decrease the clinical effects of antipsychotic drugs.
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Theoretically, concomitant use of cowhage and guanethidine might increase the risk of hypotension.
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Concomitant use can increase the risk of levodopa-related adverse effects.
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Theoretically, concomitant use of cowhage and methyldopa might increase the risk of hypotension.
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Theoretically, concomitant use of cowhage and non-selective MAOIs might increase the risk of hypertensive crisis.
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Theoretically, use of TCAs might reduce the levels and clinical effects of cowhage.
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Theoretically, horny goat weed might increase the risk of bleeding.
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In vitro research and animal research shows that horny goat weed can inhibit platelet aggregation and thrombus formation (105832). This effect has not been reported in humans.
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Theoretically, horny goat weed might increase the risk of hypotension.
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Laboratory research suggests that horny goat weed might have hypotensive effects (10346). This effect has not been reported in humans.
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Theoretically, horny goat weed might increase the effects and side effects of CYP1A2 substrates.
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In vitro, horny goat weed leaf extract inhibits CYP1A2 (97267). This effect has not been reported in humans.
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Theoretically, horny goat weed might increase the effects and side effects of CYP2B6 substrates.
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In vitro, horny goat weed leaf extract inhibits CYP2B6 (97267). This effect has not been reported in humans.
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Theoretically, horny goat weed might increase the effects and side effects of CYP3A4 substrates.
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In vitro, horny goat weed extract inhibits CYP3A4 and suppresses CYP3A4 mRNA expression (112708). This effect has not been reported in humans.
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Theoretically, concomitant use of horny goat weed with estrogens might increase their therapeutic and adverse effects.
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Theoretically, concomitant use of L-arginine and ACE inhibitors may increase the risk for hypotension and hyperkalemia.
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Combining L-arginine with some antihypertensive drugs, especially ACE inhibitors, seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916). Furthermore, ACE inhibitors can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ACE inhibitors with L-arginine may increases the risk of hyperkalemia.
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Theoretically, concomitant use of L-arginine and ARBs may increase the risk of hypotension and hyperkalemia.
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L-arginine increases nitric oxide, which causes vasodilation (7822). Combining L-arginine with ARBs seems to increase L-arginine-induced vasodilation (31854). Furthermore, ARBs can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ARBs with L-arginine may increases the risk of hyperkalemia.
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Theoretically, concomitant use of L-arginine with anticoagulant and antiplatelet drugs might have additive effects and increase the risk of bleeding.
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Theoretically, concomitant use of L-arginine might have additive effects with antidiabetes drugs.
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Theoretically, concomitant use of L-arginine and antihypertensive drugs may increase the risk of hypotension.
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L-arginine increases nitric oxide, which causes vasodilation (7822). Clinical evidence shows that L-arginine can reduce blood pressure in some individuals with hypertension (7818,10636,31871,32201,32167,32225,31923,32232,110383,110384). Furthermore, combining L-arginine with some antihypertensive drugs seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916).
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Theoretically, concurrent use of isoproterenol and L-arginine might result in additive effects and hypotension.
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Preliminary clinical evidence suggests that L-arginine enhances isoproterenol-induced vasodilation in patients with essential hypertension or a family history of essential hypertension (31932).
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Theoretically concomitant use of potassium-sparing diuretics with L-arginine may increases the risk of hyperkalemia.
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Theoretically, concurrent use of sildenafil and L-arginine might increase the risk for hypotension.
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In vivo, concurrent use of L-arginine and sildenafil has resulted in increased vasodilation (7822,8015,10636). Theoretically, concurrent use might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported (105065).
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Theoretically, concomitant use of L-arginine and testosterone might have additive effects.
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Although Panax ginseng has shown antiplatelet effects in the laboratory, it is unlikely to increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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In vitro evidence suggests that ginsenoside constituents in Panax ginseng might decrease platelet aggregation (1522,11891). However, research in humans suggests that ginseng does not affect platelet aggregation (11890). Animal research indicates low oral bioavailability of Rb1 and rapid elimination of Rg1, which might explain the discrepancy between in vitro and human research (11153). Until more is known, use with caution in patients concurrently taking anticoagulant or antiplatelet drugs.
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Theoretically, taking Panax ginseng with antidiabetes drugs might increase the risk of hypoglycemia.
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Clinical research suggests that Panax ginseng might decrease blood glucose levels (89740). Monitor blood glucose levels closely.
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Theoretically, taking Panax ginseng with caffeine might increase the risk of adverse stimulant effects.
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Theoretically, Panax ginseng might decrease levels of drugs metabolized by CYP1A1.
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In vitro research shows that Panax ginseng can induce the CYP1A1 enzyme (24104).
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Theoretically, Panax ginseng might increase levels of drugs metabolized by CYP2D6. However, research is conflicting.
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There is some evidence that Panax ginseng can inhibit the CYP2D6 enzyme by approximately 6% (1303,51331). In addition, in animal research, Panax ginseng inhibits the metabolism of dextromethorphan, a drug metabolized by CYP2D6, by a small amount (103478). However, contradictory research suggests Panax ginseng might not inhibit CYP2D6 (10847). Until more is known, use Panax ginseng cautiously in patients taking drugs metabolized by these enzymes.
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Theoretically, Panax ginseng might increase or decrease levels of drugs metabolized by CYP3A4.
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Panax ginseng may affect the clearance of drugs metabolized by CYP3A4. One such drug is imatinib. Inhibition of CYP3A4 was believed to be responsible for a case of imatinib-induced hepatotoxicity (89764). In contrast, Panax ginseng has been shown to increase the clearance of midazolam, another drug metabolized by CYP3A4 (89734,103478). Clinical research shows that Panax ginseng can reduce midazolam area under the curve by 44%, maximum plasma concentration by 26%, and time to reach maximum plasma concentration by 29% (89734). Midazolam metabolism was also increased in animals given Panax ginseng (103478). Until more is known, use Panax ginseng cautiously in combination with CYP3A4 substrates.
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Theoretically, concomitant use of large amounts of Panax ginseng might interfere with hormone replacement therapy.
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Theoretically, Panax ginseng might decrease blood levels of oral or intravenous fexofenadine.
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Animal research suggests that taking Panax ginseng in combination with oral or intravenous fexofenadine may reduce the bioavailability of fexofenadine. Some scientists have attributed this effect to the ability of Panax ginseng to increase the expression of P-glycoprotein (24101).
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Theoretically, Panax ginseng might reduce the effects of furosemide.
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There is some concern that Panax ginseng might contribute to furosemide resistance. There is one case of resistance to furosemide diuresis in a patient taking a germanium-containing ginseng product (770).
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Theoretically, Panax ginseng might increase the effects and adverse effects of imatinib.
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A case of imatinib-induced hepatotoxicity has been reported for a 26-year-old male with chronic myelogenous leukemia stabilized on imatinib for 7 years. The patient took imatinib 400 mg along with a Panax ginseng-containing energy drink daily for 3 months. Since imatinib-associated hepatotoxicity typically occurs within 2 years of initiating therapy, it is believed that Panax ginseng affected imatinib toxicity though inhibition of cytochrome P450 3A4. CYP3A4 is the primary enzyme involved in imatinib metabolism (89764).
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Theoretically, Panax ginseng use might interfere with immunosuppressive therapy.
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Panax ginseng might have immune system stimulating properties (3122).
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Theoretically, taking Panax ginseng with insulin might increase the risk of hypoglycemia.
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Clinical research suggests that Panax ginseng might decrease blood glucose levels (89740). Insulin dose adjustments might be necessary in patients taking Panax ginseng; use with caution.
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Although Panax ginseng has demonstrated variable effects on cytochrome P450 3A4 (CYP3A4), which metabolizes lopinavir, Panax ginseng is unlikely to alter levels of lopinavir/ritonavir.
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Lopinavir is metabolized by CYP3A4 and is administered with the CYP3A4 inhibitor ritonavir to increase its plasma concentrations. Panax ginseng has shown variable effects on CYP3A4 activity in humans (89734,89764). However, taking Panax ginseng (Vitamer Laboratories) 500 mg twice daily for 14 days did not alter the pharmacokinetics of lopinavir/ritonavir in 12 healthy volunteers (93578).
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Theoretically, Panax ginseng may increase the clearance of midazolam.
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Midazolam is metabolized by cytochrome P450 3A4 (CYP3A4). Clinical research suggests that Panax ginseng can reduce midazolam area under the curve by 44%, maximum plasma concentration by 26%, and time to reach maximum plasma concentration by 29% (89734). Midazolam metabolism was also increased in animals given Panax ginseng (103478).
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Theoretically, Panax ginseng can interfere with MAOI therapy.
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Theoretically, taking Panax ginseng with nifedipine might increase serum levels of nifedipine and the risk of hypotension.
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Preliminary clinical research shows that concomitant use can increase serum levels of nifedipine in healthy volunteers (22423). This might cause the blood pressure lowering effects of nifedipine to be increased when taken concomitantly with Panax ginseng.
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Theoretically, Panax ginseng has an additive effect with drugs that prolong the QT interval and potentially increase the risk of ventricular arrhythmias. However, research is conflicting.
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Theoretically, taking Panax ginseng with raltegravir might increase the risk of liver toxicity.
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A case report suggests that concomitant use of Panax ginseng with raltegravir can increase serum levels of raltegravir, resulting in elevated liver enzymes levels (23621).
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Theoretically, Panax ginseng might increase or decrease levels of selegiline, possibly altering the effects and side effects of selegiline.
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Animal research shows that taking selegiline with a low dose of Panax ginseng extract (1 gram/kg) reduces selegiline bioavailability, while taking a high dose of Panax ginseng extract (3 grams/kg) increases selegiline bioavailability (103053). More research is needed to confirm these effects.
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Theoretically, taking Panax ginseng with stimulant drugs might increase the risk of adverse stimulant effects.
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Panax ginseng might affect the clearance of warfarin. However, this interaction appears to be unlikely.
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There has been a single case report of decreased effectiveness of warfarin in a patient who also took Panax ginseng (619). However, it is questionable whether Panax ginseng was the cause of this decrease in warfarin effectiveness. Some research in humans and animals suggests that Panax ginseng does not affect the pharmacokinetics of warfarin (2531,11890,17204,24105). However, other research in humans suggests that Panax ginseng might modestly increase the clearance of the S-warfarin isomer (15176). More evidence is needed to determine whether Panax ginseng causes a significant interaction with warfarin.
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Taking tribulus with antidiabetes drugs might increase the risk of hypoglycemia.
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Clinical research shows that Tribulus can lower blood glucose levels in adults with type 2 diabetes who are taking antidiabetes medications (97327).
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Theoretically, taking tribulus with antihypertensive drugs might increase the risk of hypotension.
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Theoretically, tribulus might increase the levels and clinical effects of lithium.
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Tribulus is thought to have diuretic properties (12681). Due to these potential diuretic effects, tribulus might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of alkylating agents.
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There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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Concomitant use of vitamin E and anticoagulant or antiplatelet agents might increase the risk of bleeding.
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Vitamin E seems to inhibit of platelet aggregation and antagonize the effects of vitamin K-dependent clotting factors (4733,4844,11580,11582,11583,11584,11586,112162). These effects appear to be dose-dependent, and are probably only likely to be clinically significant with doses of at least 800 units daily (11582,11585). Mixed tocopherols, such as those found in food, might have a greater antiplatelet effect than alpha-tocopherol (10364). RRR alpha-tocopherol (natural vitamin E) 1000 IU daily antagonizes vitamin K-dependent clotting factors (11999). Advise patients to avoid high doses of vitamin E, especially in people with low vitamin K intake or other risk factors for bleeding.
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Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of antitumor antibiotics.
Details
There's concern that antioxidants could reduce the activity of antitumor antibiotic drugs such as doxorubicin, which generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.
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A specific form of vitamin E might increase absorption and levels of cyclosporine.
Details
There is some evidence that one specific formulation of vitamin E (D-alpha-tocopheryl-polyethylene glycol-1000 succinate, TPGS, tocophersolan, Liqui-E) might increase absorption of cyclosporine. This vitamin E formulation forms micelles which seems to increase absorption of cyclosporine by 40% to 72% in some patients (624,625,10368). However, this interaction is unlikely to occur with the usual forms of vitamin E.
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Theoretically, vitamin E might induce metabolism of CYP3A4, possibly reducing the levels CYP3A4 substrates.
Details
Vitamin E appears to bind with the nuclear receptor, pregnane X receptor (PXR), which results in increased expression of CYP3A4 (13499,13500). Although the clinical significance of this is not known, use caution when considering concomitant use of vitamin E and other drugs affected by these enzymes.
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Vitamin E might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.
Details
A combination of niacin and simvastatin (Zocor) effectively raises high-density lipoprotein (HDL) cholesterol levels in people with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% (7388,11537). Vitamin E alone combined with a statin does not seem to decrease HDL levels (11286,11287). It is not known whether the adverse effect on HDL is due to one of the other antioxidants or to the combination. It also is not known whether it will occur in other patient populations.
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Taking selumetinib with vitamin E can result in a total daily dose of vitamin E that exceeds safe limits and therefore might increase the risk of bleeding.
Details
Selumetinib contains 48-54 IU vitamin E per capsule (102971). The increased risk of bleeding with vitamin E appears to be dose-dependent (11582,11585,34577). Be cautious when using selumetinib in combination with supplemental vitamin E, especially in patients at higher risk of bleed, such as those with chronic conditions and those taking antiplatelet drugs (102971).
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Using vitamin E with warfarin might increase the risk of bleeding.
Details
Due to interference with production of vitamin K-dependent clotting factors, use of more than 400 IU of vitamin E daily with warfarin might increase prothrombin time (PT), INR, and the risk of bleeding, (91,92,93). At a dose of 1000 IU per day, vitamin E can antagonize vitamin K-dependent clotting factors even in people not taking warfarin (11999). Limited clinical evidence suggests that doses up to 1200 IU daily may be used safely by patients taking warfarin, but this may not be applicable in all patient populations (90).
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Theoretically, combining yohimbe bark with antiplatelet or anticoagulant drugs might have additive effects; however, this has not been reported in clinical research.
Details
Research in healthy adults shows that taking yohimbine, a constituent of yohimbe bark, in doses of 8 mg or more, seems to inhibit platelet aggregation in vitro by binding to the alpha-2 adrenoceptor (86773,86806,86835,86853). The effects of yohimbe bark itself are unclear; yohimbe bark contains 0.6% to 1.38% yohimbine, but it is unclear how much is absorbed (86862,89263).
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Theoretically, yohimbe might reduce the effects of antihypertensive drugs.
Details
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Theoretically, yohimbe might precipitate clonidine withdrawal.
Details
Chronic clonidine use can downregulate alpha-2 adrenoreceptors. Animal research and one human case report suggest that concomitant administration of yohimbine, an alpha-2 adrenoceptor antagonist, may precipitate clonidine withdrawal and lead to sympathomimetic toxicity, including hypertensive crisis (111406).
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Theoretically, yohimbe might decrease the levels and clinical effects of CYP1A2 substrates.
Details
In vitro research shows that yohimbe extract induces CYP1A2 enzymes (111404).
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CYP2D6 inhibitors may increase the levels and adverse effects of yohimbine, a constituent of yohimbe.
Details
In vitro and clinical research shows that the yohimbe bark constituent, yohimbine, is metabolized by CYP2D6 isoenzymes (105688,105697,105698). Paroxetine, a cytochrome P450 (CYP) 2D6 inhibitor, increases the maximum serum concentration of yohimbine and reduces the clearance of yohimbine compared to yohimbine alone in patients who are extensive CYP2D6 metabolizers. (114932).
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Theoretically, yohimbe might increase the levels and adverse effects of CYP2D6 substrates.
Details
In vitro research suggests that yohimbine, a constituent of yohimbe bark, inhibits CYP2D6 enzyme activity (23117).
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Theoretically, CYP3A4 inhibitors might increase the levels and adverse effects of yohimbine, a constituent of yohimbe bark.
Details
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Theoretically, yohimbe might decrease the levels and clinical effects of CYP3A4 substrates.
Details
In vitro research shows that yohimbe extract induces CYP3A4 enzymes (111404).
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Concomitant use of MAOIs with yohimbe can result in additive effects.
Details
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Paroxetine decreases the clearance of yohimbine and may increase its effects.
Details
Paroxetine, a cytochrome P450 (CYP) 2D6 inhibitor, increases the maximum serum concentration of yohimbine by about 350% and reduces the clearance of yohimbine by about 80% compared to yohimbine alone in patients who are extensive CYP2D6 metabolizers. No significant changes in pharmacokinetic parameters of yohimbine were observed with coadministration of paroxetine in patients who are poor CYP2D6 metabolizers (114932).
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Theoretically, using yohimbine with phenothiazines might have additive effects.
Details
Yohimbine, a constituent of yohimbe, has alpha-2 adrenergic antagonist effects. Theoretically, combining it with phenothiazines can cause additive alpha-2 adrenergic antagonism (19).
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Theoretically, taking yohimbe with stimulant drugs can have additive effects.
Details
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Theoretically, taking yohimbe with TCAs can increase adverse effects.
Details
A small clinical study in patients taking TCAs for at least 4 weeks shows that receiving doses of intravenous yohimbine 2.5-20 mg daily for up to 7 days precipitates severe anxiety, agitation, and tremor (105881). The effects of yohimbe bark itself are unclear; oral yohimbe bark contains 0.6% to 1.38% yohimbine, but it is unclear how much is absorbed (86862,89263).
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Amiloride can modestly reduce zinc excretion and increase zinc levels.
Details
Clinical research shows that amiloride can reduce urinary zinc excretion, especially at doses of 10 mg per day or more. This zinc-sparing effect can help to counteract zinc losses caused by thiazide diuretics, but it is unlikely to cause zinc toxicity at usual amiloride doses (830,11626,11627,11634). The other potassium-sparing diuretics, spironolactone (Aldactone) and triamterene (Dyrenium), do not seem to have a zinc-sparing effect.
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Zinc modestly reduces levels of atazanavir, although this effect does not seem to be clinically significant.
Details
Clinical research shows that zinc might decrease serum atazanavir levels by chelating with atazanavir in the gut and preventing its absorption (93578). Although a single dose of zinc sulfate (Solvazinc tablets) 125 mg orally does not affect atazanavir concentrations in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate 125 mg daily for 2 weeks reduces plasma levels of atazanavir by about 22% in these patients. However, despite this decrease, atazanavir levels still remain at high enough concentrations for the prevention of HIV virus replication (90216).
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Zinc might decrease cephalexin levels by chelating with cephalexin in the gut and preventing its absorption.
Details
A pharmacokinetic study shows that zinc sulfate 250 mg taken concomitantly with cephalexin 500 mg decreases peak levels of cephalexin by 31% and reduces the exposure to cephalexin by 27%. Also, taking zinc sulfate 3 hours before cephalexin decreases peak levels of cephalexin by 11% and reduces the exposure to cephalexin by 18%. By decreasing cephalexin levels, zinc might increase the risk of treatment failure. This effect does not occur when zinc is taken 3 hours after the cephalexin dose (94163). To avoid an interaction, advise patients take zinc sulfate 3 hours after taking cephalexin.
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Theoretically, zinc might interfere with the therapeutic effects of cisplatin.
Details
Animal research suggests that zinc stimulates tumor cell production of the protein metallothionein, which binds and inactivates cisplatin (11624,11625). It is not known whether zinc supplements or high dietary zinc intake can cause clinically significant interference with cisplatin therapy. Cisplatin might also increase zinc excretion.
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Theoretically, taking zinc along with integrase inhibitors might decrease the levels and clinical effects of these drugs.
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Zinc might reduce the levels and clinical effects of penicillamine.
Details
By forming an insoluble complex with penicillamine, zinc interferes with penicillamine absorption and activity. Zinc supplements reduce the efficacy of low-dose penicillamine (0.5-1 gram/day), but do not seem to affect higher doses (1-2.75 gram/day), provided dosing times are separated (2678,4534,11605). Advise patients to take zinc and penicillamine at least 2 hours apart.
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Zinc can decrease the levels and clinical effects of quinolones antibiotics.
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Zinc modestly reduces levels of ritonavir.
Details
Clinical research shows that zinc might reduce serum ritonavir levels by chelating with ritonavir in the gut and preventing its absorption (93578). In patients with HIV, ritonavir is taken with atazanavir to prevent the metabolism and increase the effects of atazanavir. A pharmacokinetic study shows that, in patients being treated with atazanavir/ritonavir, co-administration of zinc sulfate (Solvazinc tablets) 125 mg as a single dose or as multiple daily doses for 2 weeks reduces plasma levels of ritonavir by about 16% (90216). However, atazanavir levels still remains high enough to prevent HIV virus replication. Therefore, the decrease in ritonavir levels is not likely to be clinically significant.
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Zinc might reduce levels of tetracycline antibiotics.
Details
Tetracyclines form complexes with zinc in the gastrointestinal tract, which can reduce absorption of both the tetracycline and zinc when taken at the same time (3046,4945). Taking zinc sulfate 200 mg with tetracycline reduces absorption of the antibiotic by 30% to 40% (11615). Demeclocycline and minocycline cause a similar interaction (4945). However, doxycycline does not seem to interact significantly with zinc (11615). Advise patients to take tetracyclines at least 2 hours before, or 4-6 hours after, zinc supplements to avoid any interactions.
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Below is general information about the adverse effects of the known ingredients contained in the product Action Max XXXtreme. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, adverse effects to cowhage seem to be rare; however, a thorough safety evaluation has not been conducted.
Topically, cowhage bean pod or seed may be unsafe.
Most Common Adverse Effects:
Orally: Diarrhea, flatulence, mucosal irritation.
Topically: Erythema, pruritus, rash.
Cardiovascular ...Orally, cowhage has been reported to cause palpitations (7021,7203)
Dermatologic
...Orally, ingestion of hairs from the bean pod or seed can result in significant mucosal irritation and should be avoided.
Topically, hairs on cowhage bean pod or seed can cause severe pruritus (6898). Symptoms include severe itching, burning, inflammation, and erythematous macular rashes (18,6898). Symptoms resolve spontaneously within several hours, but may also be relieved with antihistamines (6898). The hairs can be removed from the skin by washing, but the hairs can also be retained, and transferred to other people, in fabrics and carpets. Clothing and other materials that come in contact with cowhage hairs should also be thoroughly washed (6898).
Gastrointestinal ...Orally, cowhage has been reported to cause flatulence, diarrhea, and dry mouth (7021,7203). Orally, a specific powdered cowhage seed extract (Zandopa, formerly HP-200; Zandu Pharmaceuticals) has been reported to cause nausea, abdominal distention, and vomiting in clinical research when taken in amounts of 22.5-67.5 grams divided into 2-5 doses per day (7020).
Musculoskeletal ...Orally, dyskinesia has been reported in clinical research in about 3% of patients taking a specific powdered cowhage seed extract (Zandopa, formerly HP-200; Zandu Pharmaceuticals) 22. 5-67.5 grams divided into 2-5 doses daily (7020).
Neurologic/CNS ...Orally, cowhage has been reported to cause headaches (7021,7203). Orally, insomnia has been reported in clinical research in about 3% of patients taking a specific powdered cowhage seed extract (Zandopa, formerly HP-200; Zandu Pharmaceuticals) 22.5 grams to 67.5 grams divided into 2-5 doses daily (7020).
Psychiatric ...In a case report, cowhage caused an outbreak of acute toxic psychosis. Symptoms of psychosis included confusion, giddiness, agitation, hallucinations, and paranoid delusions. The cowhage-induced psychosis was successfully treated with intravenous chlorpromazine (7021).
Other ...Orally, cowhage has been reported to cause sweating and changes in urine color, (7021,7203). Theoretically, due to the levodopa constituent, cowhage is likely to cause the same adverse effects that have been attributed to purified, prescription levodopa. Some of these side effects include elevated liver enzymes, respiratory disturbances, urinary retention, muscle cramps, and priapism (15). However, these effects have not yet been reported for cowhage.
General
...Orally, horny goat weed seems to be well tolerated when used short-term.
Most Common Adverse Effects:
Orally: Dizziness, dry mouth, nosebleed, thirst, and vomiting.
Serious Adverse Effects (Rare):
Orally: Respiratory arrest.
Cardiovascular ...A 66-year-old male with a history of cardiovascular disease developed tachyarrhythmia after taking horny goat weed for 2 weeks (13006). It is not clear if this product contained only horny goat weed or a combination of ingredients; therefore, assigning causality is not possible.
Gastrointestinal ...Orally, long-term use of horny goat weed has been associated with reports of vomiting, dry mouth, thirst, and nosebleed (10346).
Hepatic ...A case of hepatotoxicity characterized by abdominal pain, nausea, vomiting, and fever has been reported in a 40-year-old male patient with hepatitis C, after a month of taking one tablet daily of a combination product containing horny goat weed and multiple other ingredients (Enzyte, Vianda). Symptoms improved following cessation of the product, but it is not clear if they were due to horny goat weed, another ingredients, or hepatitis C (91590). An observational study over 24 years found 26 cases of drug-induced hepatoxicity associated with horny goat weed (112707).
Musculoskeletal ...Orally, large doses of horny goat weed may cause exaggeration of tendon reflexes to the point of spasm (10346).
Neurologic/CNS ...Orally, long-term use of horny goat weed has been associated with reports of dizziness (10346).
Psychiatric ...There is a case report of hypomania in a 66-year-old male who took horny goat weed for 2 weeks (13006). It is not clear if this product contained only horny goat weed or a combination of ingredients; therefore, assigning causality is not possible.
Pulmonary/Respiratory ...Orally, large doses of horny goat weed may cause respiratory arrest (10346).
General
...Oral, intravenous, and topical L-arginine are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, nausea, diarrhea, headache, insomnia, flushing.
Intravenously: Excessively rapid infusion can cause flushing, headache, nausea and vomiting, numbness, and venous irritation.
Cardiovascular ...L-arginine taken orally by pregnant patients in a nutrition bar containing other antioxidants was associated with a 36% greater risk of palpitations when compared with a placebo bar (91197). It is unclear if this effect was due to L-arginine, other ingredients, or other factors.
Dermatologic ...Orally, arginine can cause flushing, rash, and hives (3460,32138,102587,104223). The skin reactions were likely of allergic etiology as oral L-arginine has been associated with eosinophilia (32138). In one case report, intravenous administration caused allergic reactions including urticaria, periorbital edema, and pruritus (11830). Excessively rapid infusion of L-arginine has caused flushing, local venous irritation, numbness. Extravasation has caused necrosis and superficial phlebitis (3330,16817).
Gastrointestinal
...Orally, L-arginine has been reported to cause nausea, diarrhea, vomiting, dyspepsia, gastrointestinal discomfort, and bloating (1363,31855,31871,31972,31978,32261,90198,91197,96811,99243)(102587,102592).
Orally, L-arginine has been reported to cause esophagitis in at least six adolescents. Symptoms, which included pain and dysphagia, occurred within 1-3 months of treatment in most cases (102588). There are at least two cases of acute pancreatitis possibly associated with oral L-arginine. In one case, a 28-year-old male developed pancreatitis after consuming a shake containing 1.2 grams of L-arginine daily as arginine alpha-ketoglutarate. The shake also contained plant extracts, caffeine, vitamins, and other amino acids. Although there is a known relationship between L-arginine and pancreatitis in animal models, it is not clear if L-arginine was directly responsible for the occurrence of pancreatitis in this case (99266).
Intravenously, excessively rapid infusion of L-arginine has been reported to cause nausea and vomiting (3330,16817).
Musculoskeletal ...Intravenous L-arginine has been associated with lower back pain and leg restlessness (32273). Orally, L-arginine has been associated with asthenia (32138).
Neurologic/CNS ...Orally, L-arginine has been associated with headache (31855,31955,32261,91197,102587,102592), insomnia, fatigue (102587,102592), and vertigo (32150,102592).
Oncologic ...In breast cancer patients, L-arginine stimulated tumor protein synthesis, which suggests stimulated tumor growth (31917).
Pulmonary/Respiratory ...When inhaled, L-arginine can cause airway inflammation and exacerbation of airway inflammation in asthma (121). However, two studies assessing oral L-arginine in patients with asthma did not detect any adverse airway effects (31849,104223).
Renal ...Intravenously, L-arginine has been associated with natriuresis, kaliuresis, chloruresis, and systemic acidosis (32225). Orally, L-arginine can cause gout (3331,3595).
Other ...Orally, L-arginine has been associated with delayed menses, night sweats, and flushing (31855).
General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
General
...Orally, Panax ginseng is generally well tolerated when used for up to 6 months.
There is some concern about the long-term safety due to potential hormone-like effects.
Topically, no adverse effects have been reported when ginseng is used as a single ingredient. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Insomnia.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis, arrhythmia, ischemia, Stevens-Johnson syndrome.
Cardiovascular ...Panax ginseng may cause hypertension, hypotension, and edema when used orally in high doses, long-term (3353). However, single doses of Panax ginseng up to 800 mg are not associated with changes in electrocardiogram (ECG) parameters or increases in heart rate or blood pressure (96218). There is a case report of menometrorrhagia and tachyarrhythmia in a 39-year-old female who took Panax ginseng 1000-1500 mg/day orally and also applied a facial cream topically that contained Panax ginseng. Upon evaluation for menometrorrhagia, the patient also reported a history of palpitations. It was discovered that she had sinus tachycardia on ECG. However, the patient was a habitual consumer of coffee 4-6 cups/day and at the time of evaluation was also mildly anemic. The patient was advised to discontinue taking Panax ginseng. During the 6 month period following discontinuation the patient did not have any more episodes of menometrorrhagia or tachyarrhythmia (13030). Also, a case of transient ischemic attack secondary to a hypertensive crisis has been reportedly related to oral use of Panax ginseng (89402).
Dermatologic
...Orally, Panax ginseng may cause itching or an allergic response consisting of systemic rash and pruritus (89743,89760,104953,114984,114985).
Skin eruptions have also been reported with use of Panax ginseng at high dosage, long-term (3353). Uncommon side effects with oral Panax ginseng include Stevens-Johnson syndrome (596).
In one case report, a 6-year-old male with a previous diagnosis of generalized pustular psoriasis, which had been in remission for 18 months, presented with recurrent pustular lesions after consuming an unspecified dose of Panax ginseng. The patient was diagnosed with pityriasis amiantacea caused by subcorneal pustular dermatosis. Treatment with oral dapsone 25 mg daily was initiated, and symptoms resolved after 4 weeks (107748). In another case report, a 26-year-old female presented with itchy exanthem and oval erythematous lesions on the face, neck, and abdomen after consuming a decoction containing Panax ginseng, aconite, ginger, licorice, Cassia cinnamon, goldthread, and peony 400 mL twice daily for 1 week. Pityriasis rosea-like eruption was suspected, but the patient refused topical or oral antihistamines or corticosteroids. The patient continued taking the decoction but with Panax ginseng and aconite removed. After 6 days, symptoms began to resolve, and by 17 days symptom improvement was significant (114986). It is unclear if this reaction was due to Panax ginseng, aconite, the combination, or some other factor. Pityriasis rosea typically resolves spontaneously.
Topically, when a specific multi-ingredient cream preparation (SS Cream) has been applied to the glans penis, mild pain, local irritation, and burning have occurred (2537).
Endocrine
...The estrogenic effects of ginseng are controversial.
Some clinical evidence suggests it doesn't have estrogen-mediated effects (10981). However, case reports of ginseng side effects such as postmenopausal vaginal bleeding suggest estrogenic activity (590,591,592,10982,10983).
In a 12-year-old Korean-Japanese male, enlargement of both breasts with tenderness in the right breast (gynecomastia) occurred after taking red ginseng extract 500 mg daily orally for one month. Following cessation of the product, there was no further growth or pain (89733). Swollen and tender breasts also occurred in a 70-year-old female using Panax ginseng orally (590).
Gastrointestinal ...Orally, Panax ginseng can cause decreased appetite (3353), constipation, diarrhea, dyspepsia (3353,89734,103477,112841,114980,114985), abdominal pain (89734,87984,112841,114985), and nausea (589,87984). However, these effects are typically associated with long-term, high-dose usage (3353). Some evidence suggests that fermented Panax ginseng is more likely to cause abdominal pain and diarrhea when compared with unfermented Panax ginseng (112841).
Genitourinary
...Amenorrhea has been reported with oral use of Panax ginseng (3353).
Topically, when a specific multi-ingredient cream preparation (SS Cream) has been applied to the glans penis, sporadic erectile dysfunction and excessively delayed ejaculation have occurred (2537). Less commonly, patients can experience vaginal bleeding (591,592,3354,23630).
Hepatic ...It is unclear if Panax ginseng is associated with adverse hepatic effects. Cholestatic hepatitis has been reported in a 65-year old male following oral use of a combination product containing Panax ginseng and other ingredients (Prostata). However, it is unclear if this adverse effect was due to Panax ginseng, other ingredients, or the combination (598). An elevation in liver enzymes has been rarely reported in clinical research (114985).
Immunologic ...A case of anaphylaxis, with symptoms of hypotension and rash, has been reported following ingestion of a small amount of Panax ginseng syrup (11971).
Neurologic/CNS ...Orally, one of the most common side effects to Panax ginseng is insomnia (589,89734,111336,114985). Headache (594,23638,112840,114985), vertigo, euphoria, and mania (594) have also been reported. Migraine and somnolence occurred in single subjects in a clinical trial (87984). In a case report of a 46-year-old female, orobuccolingual dyskinesia occurred following oral use of a preparation containing black cohosh 20 mg and Panax ginseng 50 mg twice daily for menopausal symptoms. The patient's condition improved once the product was stopped and treatment with baclofen 40 mg and clonazepam 20 mg daily was started (89735).
General
...Orally, tribulus seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Cases of liver and kidney injury, seizures, and chronic painful erection with impaired sexual function have been reported. Pneumothorax and bronchial polyp after consuming the spine-covered tribulus fruit have been reported.
Gastrointestinal ...Orally, tribulus can cause abdominal pain, cramping, nausea, vomiting, diarrhea, and constipation (92022,92027). However, in one study, the rates of these gastrointestinal complaints were similar for patients taking tribulus and those receiving placebo (92022).
Genitourinary ...In one case report, a patient taking two tribulus tablets (unknown dose) daily for 15 days presented to the local emergency department with a painful erection lasting 72 hours. The priapism was resolved with medical management; however, post-episode sexual function was impaired (92023).
Hepatic ...In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of tribulus water (92069).
Neurologic/CNS ...Orally, tribulus has been reported to cause general excitation and insomnia. These symptoms were reversed upon discontinuation of the drug or decreasing the dose (78867). In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of tribulus water (92069).
Pulmonary/Respiratory ...In one case report, a patient developed a bilateral pneumothorax after consuming the spine-covered fruit of tribulus (818). In another case report, a patient developed a polyp in the lobar bronchus of the right interior lobe due to the presence of a tribulus fruit spine (78852).
Renal ...In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of the tribulus water (92069). In another case report, a healthy male taking one tribulus tablet (unknown dose) daily for a few months for bodybuilding purposes developed hyperbilirubinemia followed by acute kidney failure 2-3 weeks later. The patient was managed with intravenous fluids and a low-salt, low-protein diet (92025).
Other ...In one case report, gynecomastia was observed in a male weightlifter taking an herbal combination product containing tribulus. However, it is not clear if this adverse effect can be attributed to tribulus alone (78859).
General
...Orally and topically, vitamin E is generally well-tolerated.
Serious Adverse Effects (Rare):
Orally: Bleeding, hemorrhagic stroke, cardiovascular complications.
Inhaled: Vitamin E acetate is thought to be responsible for e-cigarette, or vaping, product-use associated lung injury (EVALI).
Cardiovascular
...Some evidence suggests that taking vitamin E supplements, especially greater than or equal to 400 IU taken by mouth daily for over one year, might also increase the risk of mortality in non-healthy patients (12212,13036,15305,16709,83339).
A population study shows that vitamin E use is associated with a significantly increased risk of mortality in people with a history of severe cardiovascular disease such as stroke or myocardial infarction (16709). In an analysis of clinical trials, patients who took either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) in doses of 400 IU/day or higher had an increased risk of mortality from all causes. The risk of mortality seems to increase when higher doses are used (12212). A large-scale study also suggests that patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily have an increased risk of heart failure and heart failure-related hospitalization (13036). However, in another large scale study, taking 600 IU vitamin E every other day for 10 years did not increase the risk of heart failure in healthy females over 45 years of age (90068). There is speculation that high-dose vitamin E might disrupt the normal antioxidant balance and result in pro-oxidant rather than antioxidant effects.
There is some evidence that vitamin E in combination with simvastatin (Zocor), niacin, selenium, vitamin C, and beta-carotene might lower high density lipoprotein-2 (HDL-2) by 15%. HDL-2 is considered to be the most cardioprotective component of HDL (7388). However, vitamin E and a statin alone don't seem to negatively affect HDL (11286,11287). In addition, vitamin E has been associated with increased triglycerides (85215). Although only certain isomers of vitamin E are included for determination of dietary requirements, all isomers are considered for determining safe intake levels. All the isomers are thought to potentially contribute to toxicity.
Dermatologic
...Topically, vitamin E has been associated with contact dermatitis, inflammatory reactions, and eczematous lesions (11998,85066,85285).
Dermatitis, often associated with moisturizers containing vitamin E, has a scattered generalized distribution, is more common on the face than the hands, and is more common in females with a history of atopic dermatitis. In a retrospective analysis of results of patch tests for DL-alpha-tocopherol sensitivity, 0.9% of patients had a definite positive reaction, while over 50% had a weakly positive, non-vesicular erythematous reaction (107869).
Orally, vitamin E has been associated with pruritus in one clinical trial (34596).
Subcutaneously, vitamin E has been associated with reports of lipogranuloma (85188,112331). In one case, subcutaneous injection of a specific supplement (1Super Extenze), containing mineral oil and tocopherol acetate, into the penile tissue resulted in penile disfigurement due to sclerosing lipogranuloma (85188). In another case, a 50-year-old Iranian female presented with lipogranuloma of the face, characterized by severe facial erythema, edema, and tenderness, 3 months after receiving subcutaneous injections of vitamin E to the cheeks for "facial rejuvenation." The patient had noticed initial symptoms within 3 days, and her symptoms progressively worsened over time (112331).
Gastrointestinal ...Orally, vitamin E supplementation has been associated with abdominal pain, nausea, diarrhea, or flu-like symptoms (85040,85323). Intravenously, large doses of vitamin E in premature infants are associated with an increased risk of necrotizing enterocolitis and sepsis (85083,85231).
Genitourinary ...There is contradictory evidence about the effect of vitamin E on prostate cancer risk. One large-scale population study shows that males who take a multivitamin more than 7 times per week and who also take a separate vitamin E supplement have a significantly increased risk of developing prostate cancer (15607). In a large-scale clinical trial (The SELECT trial) in males over the age of 50 years, taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily increased the risk of developing prostate cancer by 17% when compared with placebo. However, the difference in prostate cancer risk between vitamin E and placebo became significant only 3 years after patients stopped taking supplementation and were followed in an unblinded fashion. Interestingly, patients taking vitamin E plus selenium did not have a significantly increased risk of prostate cancer (17688).
Hematologic ...High doses of vitamin E might increase the risk of bleeding due to antagonism of vitamin K-dependent clotting factors and platelet aggregation. Patients with vitamin K deficiencies or taking anticoagulant or antiplatelet drugs are at a greater risk for bleeding (4098,4844,11999,34596,34538,34626,34594,112162).
Neurologic/CNS ...There is concern that vitamin E might increase the risk of hemorrhagic stroke (16708,34594,34596,108641). In one clinical study, there was a higher incidence of hemorrhagic stroke in male smokers taking all-rac-alpha-tocopherol (synthetic vitamin E) for 5-8 years compared to those not taking vitamin E (3949). Other studies lasting from 1.4-4.5 years and using either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) showed no significantly increased risk for stroke (2307,3896,3936). A meta-analysis of studies shows that vitamin E in doses of 300-800 IU daily, including both natural and synthetic forms, does not significantly affect total stroke risk. However, it significantly increases the risk of hemorrhagic stroke by 22%. This means that there will be one additional hemorrhagic stroke for every 1250 patients taking vitamin E. In contrast to this finding, the analysis also found that vitamin E significantly reduces the risk of ischemic stroke by 10%. This means that one ischemic stroke will be prevented for every 476 patients taking vitamin E (14621). In patients with moderately severe Alzheimer disease, taking vitamin E 2000 IU for 2 years has been associated with a modest, but significant, increase in falls and episodes of syncope when compared to placebo (4635).
Pulmonary/Respiratory ...When inhaled, vitamin E acetate is thought to play a role in the development of e-cigarette, or vaping, product-use associated lung injury (EVALI). Although a causal link has not yet been determined, in two case series, vitamin E acetate has been found in most bronchoalveolar lavage samples taken from the primary site of lung injury in patients with EVALI, whereas no vitamin E was found in healthy control samples. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. EVALI has resulted in death in some patients (101062,102970).
Other ...In an analysis of 3 trials, taking vitamin E 400 IU with vitamin C 1000 mg daily for 14-22 weeks during gestation appears to increase the risk of gestational hypertension by 30% compared to placebo in patients at risk of pre-eclampsia. However, the risk of pre-eclampsia itself was not increased (83450).
General
...Orally, there is limited information available about the adverse effects of yohimbe.
Yohimbine, a constituent of yohimbe, might be unsafe; most reported adverse effects are dose-related.
Most Common Adverse Effects:
Orally: Yohimbine, a constituent of yohimbe, has been associated with anxiety, agitation, diaphoresis, diarrhea, flushing, headache, hypertension, increased urination, nausea, tachycardia, tremors, vertigo, and vomiting.
Serious Adverse Effects (Rare):
Orally: Yohimbine, a constituent of yohimbe, has been associated with atrial fibrillation, hypertensive crisis, myocardial infarction, and QT interval prolongation.
Cardiovascular ...Orally, yohimbine, a constituent of yohimbe, has been associated with hypertension, especially at higher doses (3312,17465,86801,86802,86804,86811,86820,86822,86834,86856)(86786,86896). A case of hypertensive crisis was reported in a 63-year-old male taking a yohimbine-containing herbal product once daily for one month. The patient was successfully managed with intravenous nitroprusside followed by clonidine (91521). Tachycardia, fluid retention, palpitations, and chest discomfort have also been reported (3312,17465,86786,86793,86801,86802,86804,86822,86843,86854)(86856,86866,86867,86869,86871,86874,86875). Conduction abnormalities have also been reported (86856,86786). There have been some reports of myocardial infarction, atrial fibrillation, and QT interval prolongation (17465). In theory, these effects may also occur with the use of yohimbe bark extract.
Dermatologic ...Orally, yohimbine, a constituent of yohimbe, may cause rash, erythrodermic skin eruption, and exanthema (3312,3971,86804,86896,86878).
Gastrointestinal ...Orally, yohimbine, a constituent of yohimbe, may cause nausea, vomiting, increased salivation, diarrhea, and gastrointestinal distress (3970,17465,49902,86780,86781,86786,86801,86804,86824,86827)(86828,86829,86863,86878,86882,86896).
Genitourinary ...Orally, yohimbine may cause dartos contraction or decreased libido in some patients (86786,86882). A case of severe intractable priapism has been reported for a 42-year-old male who took a supplement containing yohimbe extract the previous day for sexual enhancement. Treatment with phenylephrine 400 mcg was unsuccessful at resolving the priapism, so surgical insertion of a proximal cavernosal spongiosum shunt was needed (86804).
Hematologic ...A case of drug-induced agranulocytosis has been reported following prolonged use of oral yohimbine, a constituent of yohimbe (86877).
Immunologic ...There is one report of a hypersensitivity reaction including fever; chills; malaise; itchy, scaly skin; progressive renal failure; and lupus-like syndrome associated with ingestion of a one-day dose of yohimbine, a constituent of yohimbe (6169).
Musculoskeletal ...Orally, yohimbine, a constituent of yohimbe, may cause muscle aches (86850).
Neurologic/CNS ...Orally, yohimbine, a constituent of yohimbe, has been associated with reports of general central nervous system (CNS) and autonomic excitation, tremulousness, head twitching, seizure threshold changes, enhanced brain norepinephrine release, decreased energy, dizziness, vertigo, and headache (3312,3971,86774,86779,86786,86804,86827,86857,86870,86882)(86883). Cold feet and chills have also been reported with yohimbine (86827,86896). Other adverse reactions include flushing and diaphoresis (17465). Excessive doses of yohimbine can also cause paralysis (11,18). A case of acute neurotoxicity characterized by malaise, vomiting, loss of consciousness, and seizures has been reported for a 37-year-old bodybuilder who ingested a single dose of yohimbine 5 grams. Improvement was seen within 12 hours following treatment with furosemide, labetalol, clonidine, urapidil, and gastrointestinal decontamination (86801).
Psychiatric ...Orally, yohimbine, a constituent of yohimbe, may increase malaise, fatigue, insomnia, restlessness, agitation, and anxiety (3312,3970,3971,17465,86786,86801,86804,86822,86827,86834)(86868,86878,86882,86896). In a clinical study of healthy subjects, administration of yohimbine increased impulsivity, with larger doses increasing impulsivity more than 50% (86784,86810).
Pulmonary/Respiratory ...Orally, yohimbine, a constituent of yohimbe, may cause bronchospasm, tachypnea, cough, and rhinorrhea (17465,86825,86850). A case of sinusitis characterized by pain and discomfort above both eyes has been reported for a 59-year-old male taking yohimbine 5.4 mg three times daily to treat erectile dysfunction. Symptoms resolved within 24 hours of discontinuing yohimbine. The effect was attributed to the alpha-2 adrenergic antagonist effects of yohimbine (94112). Excessive doses of yohimbine can cause respiratory depression (1118).
Renal ...Orally, yohimbine, a constituent of yohimbe, may increase urinary frequency (3312,3970,3971,17465,86804,86827,86850,86861,86882). A case of acute renal failure has been reported for a 42-year-old male taking yohimbine. Normalization of renal function was achieved following 2 weeks of treatment with corticosteroids. The renal dysfunction was attributed to yohimbine-induced systemic lupus erythematosus (6169).
General
...Orally, zinc is well tolerated in doses below the tolerable upper intake level (UL), which is 40 mg daily for adults.
Topically, zinc is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, diarrhea, metallic taste, nausea and vomiting (dose-related).
Topically: Burning, discoloration, itching, stinging, and tingling when applied to irritated tissue.
Intranasally: Bad taste, dry mouth, headache, irritation, reduced sense of smell.
Serious Adverse Effects (Rare):
Orally: There have been cases of acute renal tubular necrosis, interstitial nephritis, neurological complications, severe vomiting, and sideroblastic anemia after zinc overdose.
Intranasally: There have been cases where intranasal zinc caused permanent loss of smell (anosmia).
Dermatologic
...Topically, zinc can cause burning, stinging, itching, and tingling when applied to inflamed tissue (6911,8623,87297).
Zinc oxide can be deposited in the submucosal tissue and cause dark discoloration of the skin. This can occur with prolonged topical application to intact skin, application to eroded or ulcerated skin, or penetrating traumatic exposure, and also parenteral administration (8618).
In rare cases, oral zinc has resulted in worsened acne (104056), skin sensitivity (6592), a leishmanial reaction with a macular rash that occurred on exposed parts of the body (86935), eczema (104055), systemic contact dermatitis (109457), and the development of severe seborrheic dermatitis (86946).
Gastrointestinal
...Orally, zinc can cause nausea (338,2663,2681,6592,6700,18216,106230,106233,106227,113661), vomiting (2663,2681,6519,6592,96069,96074), a metallic or objectionable taste in the mouth (336,338,6700,11350,18216,106902,113661), abdominal cramping (6592,96069), indigestion (87227), heartburn (96069), dry mouth (87533), and mouth irritation (336,2619).
When used orally in amounts above the tolerable upper intake level, zinc may cause irritation and corrosion of the gastrointestinal tract (331,86982,87315,106902), watery diarrhea (1352), epigastric pain (2663,2681), and severe vomiting (2663,2681).
Intranasally, zinc can cause bad taste, dry mouth, and burning and irritation of the throat (8628,8629).
When used topically as a mouth rinse, zinc may cause tooth staining (90206).
Hematologic ...There is concern that high daily doses of zinc, above the tolerable upper intake level (UL) of 40 mg per day, might increase the risk of copper deficiency, potentially leading to anemia and leukopenia (7135,112473). To prevent copper deficiency, some clinicians give a small dose of copper when zinc is used in high doses, long-term (7303).
Hepatic ...There are two cases of liver deterioration in patients with Wilson disease following initiation of treatment with zinc 50-200 mg three times daily. The mechanism of action is not understood, and the event is extremely uncommon (86927,87470).
Immunologic ...Daily doses of 300 mg of supplemental zinc for 6 weeks appear to impair immune response (7135). A case of erythematosus-like syndrome, including symptoms such as fever, leg ulcers, and rash, has been reported following intake of effervescent tablets (Solvezink) containing zinc 45 mg (87506). In another case, severe neutropenia was reported after taking supplemental zinc 900 mg daily for an unknown duration (112473).
Musculoskeletal ...Orally, zinc may cause body aches in children (113661).
Neurologic/CNS
...Zinc-containing denture adhesives can cause toxicity if used more frequently than recommended for several years.
Case reports describe hyperzincemia, low copper levels, blood dyscrasias, and neurological problems, including sensory disturbances, numbness, tingling, limb weakness, and difficulty walking in patients applying denture adhesive multiple times daily for several years (17092,17093,90205,90233). Due to reports of zinc toxicity associated with use of excessive amounts of zinc-containing denture adhesives for several years, GlaxoSmithKline has reformulated Polygrip products to remove their zinc content (17092,17093).
Intranasally (8628) and orally (87534), zinc can cause headache. When used orally in amounts above the tolerable upper intake level (UL), zinc may cause central nervous system (CNS) symptoms including lethargy, fatigue, neuropathy, dizziness, and paresthesia (2663,2681,87369,87470,87533,87534,112473).
Oncologic ...There is concern that zinc might worsen prostate disease. For example, some preliminary evidence suggests that higher dietary zinc intake increases the risk for benign prostatic hyperplasia (6908). Epidemiological evidence suggests that taking more than 100 mg of supplemental zinc daily or taking supplemental zinc for 10 or more years doubles the risk of developing prostate cancer (10306). Another large-scale population study also suggests that men who take a multivitamin more than 7 times per week and who also take a separate zinc supplement have a significantly increased risk of prostate cancer-related mortality (15607). However, a large analysis of population research suggests that there is no association between zinc intake and the risk of prostate cancer (96075).
Pulmonary/Respiratory
...There are several hundred reports of complete loss of sense of smell (anosmia) that may be permanent with use of zinc gluconate nasal gel, such as Zicam (11306,11155,11707,16800,16801,17083,86999,87535).
Loss of sense of smell is thought to be dose related but has also been reported following a single application (11306,11155,11707,16800). Patients often report having sniffed deeply when applying the gel, then experiencing an immediate burning sensation, and noticing anosmia within 48 hours (17083). On June 16, 2009, the US Food and Drug Administration (FDA) advised patients not to use a specific line of commercial zinc nasal products (Zicam) after receiving 130 reports of loss of smell (16800). The manufacturer of these products had also received several hundred reports of loss of smell related to its intranasal zinc products (16801). Zinc sulfate nasal spray was used unsuccessfully for polio prophylaxis before the polio vaccine was developed. It caused loss of smell and/or taste, which was sometimes permanent (11713). Animal studies suggest that zinc sulfate negatively affects smell, possibly by damaging the olfactory epithelium and neurons (11156,11703,11704,11705,11706). Zinc gluconate nasal spray has not been tested for safety in animals or humans. The clinical studies of intranasal zinc have not described anosmia as an adverse effect, but testing was not done to see if zinc use adversely affected sense of smell (6471,8628,8629,10247). Also, these clinical studies reported tingling or burning sensation in the nostril, dry nose, nose pain, and nosebleeds.
When used in amounts above the tolerable upper intake level (UL), zinc may cause flu-like symptoms including coughing (2663).
Renal ...In overdose, zinc can cause acute renal tubular necrosis and interstitial nephritis (331,1352,87338).
Other ...Occupational inhalation of zinc oxide fumes can cause metal fume fever with symptoms including fatigue, chills, fever, myalgias, cough, dyspnea, leukocytosis, thirst, metallic taste, and salivation (331).
